32 results on '"Slavov, C"'
Search Results
2. Exploring the role of genes associated with familial cancer syndromes on the development of multiple primary tumors
- Author
-
Mitkova, A.V., primary, Dodova, R., additional, Koleva, M., additional, Andreeva, A., additional, Tzekova-Chernopolska, M., additional, Giragosyan, S., additional, Petkova, V.Y., additional, Terziev, I., additional, Rangelov, S., additional, Slavov, C., additional, Mitev, V., additional, and Kaneva, R.P., additional
- Published
- 2019
- Full Text
- View/download PDF
3. Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018)
- Author
-
Matejcic, M, Saunders, EJ, Dadaev, T, Brook, MN, Wang, K, Sheng, X, Al Olama, AA, Schumacher, FR, Ingles, SA, Govindasami, K, Benlloch, S, Berndt, SI, Albanes, D, Koutros, S, Muir, K, Stevens, VL, Gapstur, SM, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Pashayan, N, Schleutker, J, Wolk, A, West, C, Mucci, L, Kraft, P, Cancel-Tassin, G, Sorensen, KD, Maehle, L, Grindedal, EM, Strom, SS, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Bensen, JT, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, LA, Pandha, H, Thibodeau, SN, Schaid, DJ, Wiklund, F, Chanock, SJ, Easton, DF, Eeles, RA, Kote-Jarai, Z, Conti, DV, Haiman, CA, Henderson, BE, Stern, MC, Thwaites, A, Guy, M, Whitmore, I, Morgan, A, Fisher, C, Hazel, S, Livni, N, Cook, M, Fachal, L, Weinstein, S, Freeman, LEB, Hoover, RN, Machiela, MJ, Lophatananon, A, Carter, BD, Goodman, P, Moya, L, Srinivasan, S, Kedda, M-A, Yeadon, T, Eckert, A, Eklund, M, Cavalli-Bjoerkman, C, Dunning, AM, Sipeky, C, Hakansson, N, Elliott, R, Ranu, H, Giovannucci, E, Turman, C, Hunter, DJ, Cussenot, O, Orntoft, TF, Lane, A, Lewis, SJ, Davis, M, Key, TJ, Brown, P, Kulkarni, GS, Zlotta, AR, Fleshner, NE, Finelli, A, Mao, X, Marzec, J, MacInnis, RJ, Milne, R, Hopper, JL, Aguado, M, Bustamante, M, Castano-Vinyals, G, Gracia-Lavedan, E, Cecchini, L, Stampfer, M, Ma, J, Sellers, TA, Geybels, MS, Park, H, Zachariah, B, Kolb, S, Wokolorczyk, D, Lubinski, J, Kluzniak, W, Nielsen, SF, Weisher, M, Cuk, K, Vogel, W, Luedeke, M, Logothetis, CJ, Paulo, P, Cardoso, M, Maia, S, Silva, MP, Steele, L, Ding, YC, De Meerleer, G, De Langhe, S, Thierens, H, Lim, J, Tan, MH, Ong, AT, Lin, DW, Kachakova, D, Mitkova, A, Mitev, V, Parliament, M, Jenster, G, Bangma, C, Schroder, FH, Truong, T, Koudou, YA, Michael, A, Kierzek, A, Karlsson, A, Broms, M, Wu, H, Aukim-Hastie, C, Tillmans, L, Riska, S, McDonnell, SK, Dearnaley, D, Spurdle, A, Gardiner, R, Hayes, V, Butler, L, Taylor, R, Papargiris, M, Saunders, P, Kujala, P, Talala, K, Taari, K, Bentzen, S, Hicks, B, Vogt, A, Hutchinson, A, Cox, A, George, A, Toi, A, Evans, A, Van der Kwast, TH, Imai, T, Saito, S, Zhao, S-C, Ren, G, Zhang, Y, Yu, Y, Wu, Y, Wu, J, Zhou, B, Pedersen, J, Lobato-Busto, R, Manuel Ruiz-Dominguez, J, Mengual, L, Alcaraz, A, Pow-Sang, J, Herkommer, K, Vlahova, A, Dikov, T, Christova, S, Carracedo, A, Tretarre, B, Rebillard, X, Mulot, C, Adolfsson, J, Stattin, P, Johansson, J-E, Martin, RM, Thompson, IM, Chambers, S, Aitken, J, Horvath, L, Haynes, A-M, Tilley, W, Risbridger, G, Aly, M, Nordstrom, T, Pharoah, P, Tammela, TLJ, Murtola, T, Auvinen, A, Burnet, N, Barnett, G, Andriole, G, Klim, A, Drake, BF, Borre, M, Kerns, S, Ostrer, H, Zhang, H-W, Cao, G, Lin, J, Ling, J, Li, M, Feng, N, Li, J, He, W, Guo, X, Sun, Z, Wang, G, Guo, J, Southey, MC, FitzGerald, LM, Marsden, G, Gomez-Caamano, A, Carballo, A, Peleteiro, P, Calvo, P, Szulkin, R, Llorca, J, Dierssen-Sotos, T, Gomez-Acebo, I, Lin, H-Y, Ostrander, EA, Bisbjerg, R, Klarskov, P, Roder, MA, Iversen, P, Holleczek, B, Stegmaier, C, Schnoeller, T, Bohnert, P, John, EM, Ost, P, Teo, S-H, Gamulin, M, Kulis, T, Kastelan, Z, Slavov, C, Popov, E, Van den Broeck, T, Joniau, S, Larkin, S, Esteban Castelao, J, Martinez, ME, Van Schaik, RHN, Xu, J, Lindstrom, S, Riboli, E, Berry, C, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Freedman, M, Cenee, S, Sanchez, M, and Commission of the European Communities
- Subjects
Multidisciplinary Sciences ,Science & Technology ,MD Multidisciplinary ,Science & Technology - Other Topics ,PRACTICAL Consortium - Abstract
Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-06863-1, published online 5 November 2018.
- Published
- 2019
4. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
- Author
-
Dadaev, T, Saunders, EJ, Newcombe, PJ, Anokian, E, Leongamornlert, DA, Brook, MN, Cieza-Borrella, C, Mijuskovic, M, Wakerell, S, Olama, AAA, Schumacher, FR, Berndt, SI, Benlloch, S, Ahmed, M, Goh, C, Sheng, X, Zhang, Z, Muir, K, Govindasami, K, Lophatananon, A, Stevens, VL, Gapstur, SM, Carter, BD, Tangen, CM, Goodman, P, Thompson, IM, Batra, J, Chambers, S, Moya, L, Clements, J, Horvath, L, Tilley, W, Risbridger, G, Gronberg, H, Aly, M, Nordström, T, Pharoah, P, Pashayan, N, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Albanes, D, Weinstein, S, Wolk, A, Hakansson, N, West, C, Dunning, AM, Burnet, N, Mucci, L, Giovannucci, E, Andriole, G, Cussenot, O, Cancel-Tassin, G, Koutros, S, Freeman, LEB, Sorensen, KD, Orntoft, TF, Borre, M, Maehle, L, Grindedal, EM, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Travis, RC, Key, TJ, Hamilton, RJ, Fleshner, NE, Finelli, A, Ingles, SA, Stern, MC, Rosenstein, B, Kerns, S, Ostrer, H, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Guo, X, Wang, G, Sun, Z, Giles, GG, Southey, MC, Macinnis, RJ, Fitzgerald, LM, Kibel, AS, Drake, BF, Vega, A, Gómez-Caamaño, A, Fachal, L, Szulkin, R, Eklund, M, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Penney, KL, Stampfer, M, Park, JY, Sellers, TA, Lin, H-Y, Stanford, JL, Cybulski, C, Wokolorczyk, D, Lubinski, J, Ostrander, EA, Geybels, MS, Nordestgaard, BG, Nielsen, SF, Weisher, M, Bisbjerg, R, Røder, MA, Iversen, P, Brenner, H, Cuk, K, Holleczek, B, Maier, C, Luedeke, M, Schnoeller, T, Kim, J, Logothetis, CJ, John, EM, Teixeira, MR, Paulo, P, Cardoso, M, Neuhausen, SL, Steele, L, Ding, YC, De Ruyck, K, De Meerleer, G, Ost, P, Razack, A, Lim, J, Teo, S-H, Lin, DW, Newcomb, LF, Lessel, D, Gamulin, M, Kulis, T, Kaneva, R, Usmani, N, Slavov, C, Mitev, V, Parliament, M, Singhal, S, Claessens, F, Joniau, S, Van Den Broeck, T, Larkin, S, Townsend, PA, Aukim-Hastie, C, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Roobol, MJ, Jenster, G, Van Schaik, RHN, Menegaux, F, Truong, T, Koudou, YA, Xu, J, Khaw, K-T, Cannon-Albright, L, Pandha, H, Michael, A, Kierzek, A, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Lindstrom, S, Turman, C, Ma, J, Hunter, DJ, Riboli, E, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Hoover, RN, Machiela, MJ, Kraft, P, Consortium, Practical (Prostate Cancer Association Group To Investigate Cancer-Associated Alterations In The Genome), Freedman, M, Wiklund, F, Chanock, S, Henderson, BE, Easton, DF, Haiman, CA, Eeles, RA, Conti, DV, Kote-Jarai, Z, Dadaev, Tokhir [0000-0002-8268-0438], Leongamornlert, Daniel A [0000-0002-3486-3168], Brook, Mark N [0000-0002-8969-2378], Olama, Ali Amin Al [0000-0002-7178-3431], Schumacher, Fredrick R [0000-0002-3073-7463], Muir, Kenneth [0000-0001-6429-988X], Batra, Jyotsna [0000-0003-4646-6247], Nordström, Tobias [0000-0003-4915-7546], Pharoah, Paul [0000-0001-8494-732X], Pashayan, Nora [0000-0003-0843-2468], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Wolk, Alicja [0000-0001-7387-6845], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Sorensen, Karina Dalsgaard [0000-0002-4902-5490], Kerns, Sarah [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Fachal, Laura [0000-0002-7256-9752], Kogevinas, Manolis [0000-0002-9605-0461], Nordestgaard, Børge G [0000-0002-1954-7220], Lim, Jasmine [0000-0002-7501-1834], Truong, Thérèse [0000-0002-2943-6786], Xu, Jianfeng [0000-0002-1343-8752], Easton, Douglas F [0000-0003-2444-3247], Eeles, Rosalind A [0000-0002-3698-6241], Apollo - University of Cambridge Repository, National Institutes of Health, Urology, and Clinical Chemistry
- Subjects
Male ,Risk ,Science ,GENETIC ,Quantitative Trait Loci ,Black People ,PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium ,urologic and male genital diseases ,ANNOTATION ,Polymorphism, Single Nucleotide ,Article ,White People ,REGION ,GENETIC ASSOCIATION ,SDG 3 - Good Health and Well-being ,MD Multidisciplinary ,Medicine and Health Sciences ,ELEMENTS ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,lcsh:Science ,Medicinsk genetik ,MODEL SELECTION ,BAYESIAN FRAMEWORK ,Cancer och onkologi ,Science & Technology ,Chromosome Mapping ,Prostatic Neoplasms ,Bayes Theorem ,Molecular Sequence Annotation ,ASSOCIATION ,JOINT ANALYSIS ,RISK LOCI ,STATISTICS ,Multidisciplinary Sciences ,Cancer and Oncology ,Multivariate Analysis ,Science & Technology - Other Topics ,lcsh:Q ,Medical Genetics ,Algorithms ,VARIABLE-SELECTION ,Genome-Wide Association Study - Abstract
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling., Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.
- Published
- 2018
5. Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types
- Author
-
Kar, SP, Beesley, J, Al Olama, AA, Michailidou, K, Tyrer, J, Kote-Jarai, ZA, Lawrenson, K, Lindstrom, S, Ramus, SJ, Thompson, DJ, Kibel, AS, Dansonka-Mieszkowska, A, Michael, A, Dieffenbach, AK, Gentry-Maharaj, A, Whittemore, AS, Wolk, A, Monteiro, A, Peixoto, A, Kierzek, A, Cox, A, Rudolph, A, Gonzalez-Neira, A, Wu, AH, Lindblom, A, Swerdlow, A, Ziogas, A, Ekici, AB, Burwinkel, B, Karlan, BY, Nordestgaard, BG, Blomqvist, C, Phelan, C, McLean, C, Pearce, CL, Vachon, C, Cybulski, C, Slavov, C, Stegmaier, C, Maier, C, Ambrosone, CB, Hogdall, CK, Teerlink, CC, Kang, D, Tessier, DC, Schaid, DJ, Stram, DO, Cramer, DW, Neal, DE, Eccles, D, Flesch-Janys, D, Velez Edwards, DR, Wokozorczyk, D, Levine, DA, Yannoukakos, D, Sawyer, EJ, Bandera, EV, Poole, EM, Goode, EL, Khusnutdinova, E, Hogdall, E, Song, F, Bruinsma, F, Heitz, F, Modugno, F, Hamdy, FC, Wiklund, F, Giles, GG, Olsson, H, Wildiers, H, and Ulmer, HU
- Abstract
© 2016 American Association for Cancer Research. Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.
- Published
- 2016
6. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
- Author
-
Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Zheng, W, Pettaway, CA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, John, EM, Murphy, AB, Signorello, LB, Carpten, J, Leske, MC, Wu, S-Y, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Southey, MC, Fitzgerald, LM, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schleutker, J, Wahlfors, T, Tammela, TLJ, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Stanford, JL, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Teerlink, C, Brenner, H, Dieffenbach, AK, Arndt, V, Park, JY, Sellers, TA, Lin, H-Y, Slavov, C, Kaneva, R, Mitev, V, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Pandha, H, Michael, A, Paulo, P, Maia, S, Kierzek, A, Conti, DV, Albanes, D, Berg, C, Berndt, SI, Campa, D, Crawford, ED, Diver, WR, Gapstur, SM, Gaziano, JM, Giovannucci, E, Hoover, R, Hunter, DJ, Johansson, M, Kraft, P, Le Marchand, L, Lindstrom, S, Navarro, C, Overvad, K, Riboli, E, Siddiq, A, Stevens, VL, Trichopoulos, D, Vineis, P, Yeager, M, Trynka, G, Raychaudhuri, S, Schumacher, FR, Price, AL, Freedman, ML, Haiman, CA, Pasaniuc, B, Cook, M, Guy, M, Govindasami, K, Leongamornlert, D, Sawyer, EJ, Wilkinson, R, Saunders, EJ, Tymrakiewicz, M, Dadaev, T, Morgan, A, Fisher, C, Hazel, S, Livni, N, Lophatananon, A, Pedersen, J, Hopper, JL, Adolfson, J, Stattin, P, Johansson, J-E, Cavalli-Bjoerkman, C, Karlsson, A, Broms, M, Auvinen, A, Kujala, P, Maeaettaenen, L, Murtola, T, Taari, K, Weischer, M, Nielsen, SF, Klarskov, P, Roder, A, Iversen, P, Wallinder, H, Gustafsson, S, Cox, A, Brown, P, George, A, Marsden, G, Lane, A, Davis, M, Tillmans, L, Riska, S, Wang, L, Rinckleb, A, Lubiski, J, Stegmaier, C, Pow-Sang, J, Park, H, Radlein, S, Rincon, M, Haley, J, Zachariah, B, Kachakova, D, Popov, E, Mitkova, A, Vlahova, A, Dikov, T, Christova, S, Heathcote, P, Wood, G, Malone, G, Saunders, P, Eckert, A, Yeadon, T, Kerr, K, Collins, A, Turner, M, Srinivasan, S, Kedda, M-A, Alexander, K, Omara, T, Wu, H, Henrique, R, Pinto, P, Santos, J, Barros-Silva, J, and Consortium, PRACTICAL
- Subjects
urologic and male genital diseases - Abstract
Although genome-wide association studies have identified over 100 risk loci that explain ~33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
- Published
- 2016
7. 2029P - Exploring the role of genes associated with familial cancer syndromes on the development of multiple primary tumors
- Author
-
Mitkova, A.V., Dodova, R., Koleva, M., Andreeva, A., Tzekova-Chernopolska, M., Giragosyan, S., Petkova, V.Y., Terziev, I., Rangelov, S., Slavov, C., Mitev, V., and Kaneva, R.P.
- Published
- 2019
- Full Text
- View/download PDF
8. Malignant melanoma of glans penis and prepuce treated with organ-preserving surgical procedure
- Author
-
Slavov, C., Venkov, G., Velikova, K., Christova, S., Elenko Popov, and Tsankov, N.
- Subjects
Diagnosis, Differential ,Male ,Humans ,Melanoma ,Penile Neoplasms ,malignant melanoma ,glans penis ,prepuce ,organ-preserving surgical procedure ,buccal mucosa ,Aged - Abstract
The authors present a case of malignant melanoma of glans penis and prepuce. An organ-preserving operative procedure using buccal mucosa was performed with subsequent inguino-femoral modified lymphadenectomy. There was no disease progression during the follow-up period of twelve months.
- Published
- 2009
9. Evaluation of the clinical value of the newly identified urine biomarker HIST1H4K for diagnosis and prognosis of prostate cancer in Bulgarian patients
- Author
-
Kachakova, D., Mitkova, A., Popov, E., Beltcheva, O., Aleksandrina Vlahova, Dikov, T., Hristova, S., Mitev, V., Slavov, C., and Kaneva, R.
- Subjects
Adult ,Aged, 80 and over ,Male ,Adolescent ,Prostatic Hyperplasia ,Prostatic Neoplasms ,DNA Methylation ,Middle Aged ,Prostate-Specific Antigen ,Prognosis ,Real-Time Polymerase Chain Reaction ,Histones ,Young Adult ,Case-Control Studies ,Biomarkers, Tumor ,Humans ,Neoplasm Grading ,Neoplasm Metastasis ,Promoter Regions, Genetic ,Aged ,Follow-Up Studies ,Neoplasm Staging - Abstract
Searching for diagnostic and prognostic biomarkers for prostate cancer (PC) is main public health priority. DNA methylation in body fluids is a stable, easily detectable and promising PC biomarker. The major advantages of urine-based assays are their noninvasive nature and the ability to monitor PC with heterogeneous foci. The aim of this study was to determine the diagnostic value of the recently identified candidate PC biomarker HIST1H4K.We investigated DNA methylation of HIST1H4K in urine samples from 57 PC patients, 29 controls with benign prostatic hyperplasia (BPH) and 50 young asymptomatic men (YAM) by MethyLight real-time PCR.The frequency of HIST1H4K promoter hypermethylation significantly discriminated PC patients from YAM (AUC =0.763; 95% CI 0.672-0.839; p0.0001), but did not show any statistical difference between PC patients and BPH controls (AUC=0.513, 95% CI 0.402-0.622; p=0.8255). HIST1H4K could not outperform the prostatic specific antigen (PSA) in our sample (AUC=0.785; 95% CI 0.679-0.870; p0.0001). Methylation of HIST1H4K showed significant correlation with aging (r=0.5418; p0.0001), but with no other clinicopathological characteristics.The results suggest that the promoter hypermethylation of HIST1H4K is rather due to aging than related to prostate carcinogenesis. To elucidate this observation analysis of larger samples is needed.
10. Contemporary Molecular Markers for Predicting Systemic Treatment Response in Urothelial Bladder Cancer: A Narrative Review.
- Author
-
Dimitrov G, Mangaldzhiev R, Slavov C, and Popov E
- Abstract
The search for dependable molecular biomarkers to enhance routine clinical practice is a compelling challenge across all oncology fields. Urothelial bladder carcinoma, known for its significant heterogeneity, presents difficulties in predicting responses to systemic therapies and outcomes post-radical cystectomy. Recent advancements in molecular cancer biology offer promising avenues to understand the disease's biology and identify emerging predictive biomarkers. Stratifying patients based on their recurrence risk post-curative treatment or predicting the efficacy of conventional and targeted therapies could catalyze personalized treatment selection and disease surveillance. Despite progress, reliable molecular biomarkers to forecast responses to systemic agents, in neoadjuvant, adjuvant, or palliative treatment settings, are still lacking, underscoring an urgent unmet need. This review aims to delve into the utilization of current and emerging molecular signatures across various stages of urothelial bladder carcinoma to predict responses to systemic therapy.
- Published
- 2024
- Full Text
- View/download PDF
11. Precision Medicine in Castration-Resistant Prostate Cancer: Advances, Challenges, and the Landscape of PARPi Therapy-A Narrative Review.
- Author
-
Dimitrov G, Mangaldzhiev R, Slavov C, and Popov E
- Subjects
- Male, Female, Humans, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Precision Medicine, BRCA2 Protein genetics, Poly(ADP-ribose) Polymerases, BRCA1 Protein genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
After recent approvals, poly-adenosine diphosphate [ADP]-ribose polymerase inhibitors (PARPis) have emerged as a frontline treatment for metastatic castration-resistant prostate cancer (mCRPC). Unlike their restricted use in breast or ovarian cancers, where approval is limited to those with BRCA1/2 alterations, PARPis in mCRPC are applied across a broader spectrum of genetic aberrations. Key findings from the phase III PROPEL trial suggest that PARPis' accessibility may broaden, even without mandatory testing. An increasing body of evidence underscores the importance of distinct alterations in homologous recombination repair (HRR) genes, revealing unique sensitivities to PARPis. Nonetheless, despite the initial effectiveness of PARPis in treating BRCA-mutated tumors, resistance to therapy is frequently encountered. This review aims to discuss patient stratification based on biomarkers and genetic signatures, offering insights into the nuances of first-line PARPis' efficacy in the intricate landscape of mCRPC.
- Published
- 2024
- Full Text
- View/download PDF
12. Watching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography.
- Author
-
Wranik M, Weinert T, Slavov C, Masini T, Furrer A, Gaillard N, Gioia D, Ferrarotti M, James D, Glover H, Carrillo M, Kekilli D, Stipp R, Skopintsev P, Brünle S, Mühlethaler T, Beale J, Gashi D, Nass K, Ozerov D, Johnson PJM, Cirelli C, Bacellar C, Braun M, Wang M, Dworkowski F, Milne C, Cavalli A, Wachtveitl J, Steinmetz MO, and Standfuss J
- Subjects
- Crystallography, Ligands, Crystallography, X-Ray, Tubulin metabolism, Microtubules metabolism
- Abstract
The binding and release of ligands from their protein targets is central to fundamental biological processes as well as to drug discovery. Photopharmacology introduces chemical triggers that allow the changing of ligand affinities and thus biological activity by light. Insight into the molecular mechanisms of photopharmacology is largely missing because the relevant transitions during the light-triggered reaction cannot be resolved by conventional structural biology. Using time-resolved serial crystallography at a synchrotron and X-ray free-electron laser, we capture the release of the anti-cancer compound azo-combretastatin A4 and the resulting conformational changes in tubulin. Nine structural snapshots from 1 ns to 100 ms complemented by simulations show how cis-to-trans isomerization of the azobenzene bond leads to a switch in ligand affinity, opening of an exit channel, and collapse of the binding pocket upon ligand release. The resulting global backbone rearrangements are related to the action mechanism of microtubule-destabilizing drugs., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
13. Ultrafast Photoconversion Dynamics of the Knotless Phytochrome Syn Cph2.
- Author
-
Fischer T, van Wilderen LJGW, Gnau P, Bredenbeck J, Essen LO, Wachtveitl J, and Slavov C
- Subjects
- Kinetics, Light, Models, Molecular, Photoreceptors, Microbial chemistry, Photoreceptors, Microbial metabolism, Protein Conformation, Spectrum Analysis, Structure-Activity Relationship, Photochemical Processes, Phytochrome chemistry, Phytochrome metabolism
- Abstract
The family of phytochrome photoreceptors contains proteins with different domain architectures and spectral properties. Knotless phytochromes are one of the three main subgroups classified by their distinct lack of the PAS domain in their photosensory core module, which is in contrast to the canonical PAS-GAF-PHY array. Despite intensive research on the ultrafast photodynamics of phytochromes, little is known about the primary kinetics in knotless phytochromes. Here, we present the ultrafast P
r ⇆ Pfr photodynamics of Syn Cph2, the best-known knotless phytochrome. Our results show that the excited state lifetime of Pr * (~200 ps) is similar to bacteriophytochromes, but much longer than in most canonical phytochromes. We assign the slow Pr * kinetics to relaxation processes of the chromophore-binding pocket that controls the bilin chromophore's isomerization step. The Pfr photoconversion dynamics starts with a faster excited state relaxation than in canonical phytochromes, but, despite the differences in the respective domain architectures, proceeds via similar ground state intermediate steps up to Meta-F. Based on our observations, we propose that the kinetic features and overall dynamics of the ultrafast photoreaction are determined to a great extent by the geometrical context (i.e., available space and flexibility) within the binding pocket, while the general reaction steps following the photoexcitation are most likely conserved among the red/far-red phytochromes.- Published
- 2021
- Full Text
- View/download PDF
14. Design of High-Performance Pyridine/Quinoline Hydrazone Photoswitches.
- Author
-
Mravec B, Budzák Š, Medved' M, Pašteka LF, Slavov C, Saßmannshausen T, Wachtveitl J, Kožíšek J, Hegedüsová L, Filo J, and Cigáň M
- Abstract
The design of P-type photoswitches with thermal stability of the metastable form of hundreds of years that would efficiently transform using excitation wavelengths above 350 nm remains a challenge in the field of photochromism. In this regard, we designed and synthesized an extended set of 13 pyridine/quinoline hydrazones and systematically investigated the structure-property relationships, defining their kinetic and photoswitching parameters. We show that the operational wavelengths of the pyridine hydrazone structural motif can be effectively shifted toward the visible region without simultaneous loss of their high thermal stability. Furthermore, we characterized the ground-state and excited-state potential energy surfaces with quantum-chemical calculations and ultrafast transient absorption spectroscopy, which allowed us to rationalize both the thermal and photochemical reaction mechanisms of the designed hydrazones. Whereas introducing an electron-withdrawing pyridyl moiety in benzoylpyridine hydrazones leads to thermal stabilities exceeding 200 years, extended π-conjugation in naphthoylquinoline hydrazones pushes the absorption maxima toward the visible spectral region. In either case, the compounds retain highly efficient photoswitching characteristics. Our findings open a route to the rational design of a new family of hydrazone-based P-type photoswitches with high application potential in photonics or photopharmacology.
- Published
- 2021
- Full Text
- View/download PDF
15. Clinical impact of copy number variation changes in bladder cancer samples.
- Author
-
Spasova V, Mladenov B, Rangelov S, Hammoudeh Z, Nesheva D, Serbezov D, Staneva R, Hadjidekova S, Ganev M, Balabanski L, Vazharova R, Slavov C, Toncheva D, and Antonova O
- Abstract
The aim of the present study was to detect copy number variations (CNVs) related to tumour progression and metastasis of urothelial carcinoma through whole-genome scanning. A total of 30 bladder cancer samples staged from pTa to pT4 were included in the study. DNA was extracted from freshly frozen tissue via standard phenol-chloroform extraction and CNV analysis was performed on two alternative platforms (CytoChip Oligo aCGH, 4x44K and Infinium OncoArray-500K BeadChip; Illumina, Inc.). Data were analysed with BlueFuse Multi software and Karyostudio, respectively. The results highlight the role of genomic imbalances in regions containing genes with metastatic and proliferative potential for tumour invasion. A high level of genomic instability in uroepithelial tumours was observed and a total of 524 aberrations, including 175 losses and 349 gains, were identified. The most prevalent genetic imbalances affected the following regions: 1p, 1q, 2q, 4p, 4q, 5p, 5q, 6p, 6q, 7q, 8q, 9p, 9q, 10p, 10q, 11q, 13q and 17q. High-grade tumours more frequently harboured genomic imbalances (n=227) than low-grade tumours (n=103). A total of 36 CNVs in high-grade bladder tumours were detected in chromosomes 1-5, 8-11, 14, 17, 19 and 20. Furthermore, five loss of heterozygosity variants containing 176 genes were observed in high-grade bladder cancer and may be used as potential targets for precision therapy. Revealing specific chromosomal regions related to the metastatic potential of uroepithelial tumours may lay a foundation for implementing molecular CNV profiling of bladder tumours as part of a routine progression risk estimation strategy, thus expanding the personalized therapeutic approach., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Spasova et al.)
- Published
- 2021
- Full Text
- View/download PDF
16. Temperature Dependence of the Krokinobacter rhodopsin 2 Kinetics.
- Author
-
Eberhardt P, Slavov C, Sörmann J, Bamann C, Braun M, and Wachtveitl J
- Subjects
- Kinetics, Light, Rhodopsins, Microbial, Temperature, Flavobacteriaceae, Rhodopsin
- Abstract
We investigated the temperature-dependent kinetics of the light-driven Na
+ pump Krokinobacter rhodopsin 2 (KR2) at Na+ -pumping conditions. The recorded microsecond flash photolysis data were subjected to detailed global target analysis, employing Eyring constraints and spectral decomposition. The analysis resulted in the kinetic rates, the composition of the different photocycle equilibria, and the spectra of the involved photointermediates. Our results show that with the temperature increase (from 10 to 40°C), the overall photocycle duration is accelerated by a factor of 6, with the L-to-M transition exhibiting an impressive 40-fold increase. It follows from the analysis that in KR2 the chromophore and the protein scaffold are more kinetically decoupled than in other microbial rhodopsins. We link this effect to the rigidity of the retinal protein environment. This kinetic decoupling should be considered in future studies and could potentially be exploited for fine-tuning biotechnological applications., (Copyright © 2020 Biophysical Society. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
17. The effect of sample size on polygenic hazard models for prostate cancer.
- Author
-
Karunamuni RA, Huynh-Le MP, Fan CC, Eeles RA, Easton DF, Kote-Jarai Z, Amin Al Olama A, Benlloch Garcia S, Muir K, Gronberg H, Wiklund F, Aly M, Schleutker J, Sipeky C, Tammela TLJ, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright L, Brenner H, Schöttker B, Holleczek B, Park JY, Sellers TA, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Mills IG, Andreassen OA, Dale AM, and Seibert TM
- Subjects
- Clinical Trials as Topic, Humans, Male, Models, Genetic, Proportional Hazards Models, Sample Size, Genome-Wide Association Study methods, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics
- Abstract
We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR
98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.- Published
- 2020
- Full Text
- View/download PDF
18. The interplay between chromophore and protein determines the extended excited state dynamics in a single-domain phytochrome.
- Author
-
Slavov C, Fischer T, Barnoy A, Shin H, Rao AG, Wiebeler C, Zeng X, Sun Y, Xu Q, Gutt A, Zhao KH, Gärtner W, Yang X, Schapiro I, and Wachtveitl J
- Subjects
- Bile Pigments chemistry, Bile Pigments metabolism, Crystallography, X-Ray, Isomerism, Kinetics, Models, Molecular, Nostoc metabolism, Photochemical Processes, Photoreceptors, Microbial chemistry, Photoreceptors, Microbial metabolism, Protein Conformation, Spectrum Analysis, Structure-Activity Relationship, Phytochrome chemistry, Phytochrome metabolism
- Abstract
Phytochromes are a diverse family of bilin-binding photoreceptors that regulate a wide range of physiological processes. Their photochemical properties make them attractive for applications in optogenetics and superresolution microscopy. Phytochromes undergo reversible photoconversion triggered by the Z ⇄ E photoisomerization about the double bond in the bilin chromophore. However, it is not fully understood at the molecular level how the protein framework facilitates the complex photoisomerization dynamics. We have studied a single-domain bilin-binding photoreceptor All2699g1 ( Nostoc sp. PCC 7120) that exhibits photoconversion between the red light-absorbing (P
r ) and far red-absorbing (Pfr ) states just like canonical phytochromes. We present the crystal structure and examine the photoisomerization mechanism of the Pr form as well as the formation of the primary photoproduct Lumi-R using time-resolved spectroscopy and hybrid quantum mechanics/molecular mechanics simulations. We show that the unusually long excited state lifetime (broad lifetime distribution centered at ∼300 picoseconds) is due to the interactions between the isomerizing pyrrole ring D and an adjacent conserved Tyr142. The decay kinetics shows a strongly distributed character which is imposed by the nonexponential protein dynamics. Our findings offer a mechanistic insight into how the quantum efficiency of the bilin photoisomerization is tuned by the protein environment, thereby providing a structural framework for engineering bilin-based optical agents for imaging and optogenetics applications., Competing Interests: The authors declare no competing interest.- Published
- 2020
- Full Text
- View/download PDF
19. Computational design of a molecular triple photoswitch for wavelength-selective control.
- Author
-
Yang C, Slavov C, Wegner HA, Wachtveitl J, and Dreuw A
- Abstract
A small single molecule with multiple photoswitchable subunits, selectively and independently controllable by light of different wavelengths, is highly attractive for applications in multi-responsive materials and biological sciences. Herein, triple photoswitches are presented consisting of three independent azobenzene (AB) subunits that share a common central phenyl ring: the meta -trisazobenzenes (MTA). It is the unique meta-connectivity pattern leading to decoupling of all azo-subunits although they do overlap spatially. Based on this pattern, we design a triple MTA photoswitch, as proof-of-principle, with three different, electronically independent AB branches on the computer, which can be individually photo-excited to trigger ultra-fast E → Z isomerization at the selected AB branch.
- Published
- 2018
- Full Text
- View/download PDF
20. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.
- Author
-
Dadaev T, Saunders EJ, Newcombe PJ, Anokian E, Leongamornlert DA, Brook MN, Cieza-Borrella C, Mijuskovic M, Wakerell S, Olama AAA, Schumacher FR, Berndt SI, Benlloch S, Ahmed M, Goh C, Sheng X, Zhang Z, Muir K, Govindasami K, Lophatananon A, Stevens VL, Gapstur SM, Carter BD, Tangen CM, Goodman P, Thompson IM Jr, Batra J, Chambers S, Moya L, Clements J, Horvath L, Tilley W, Risbridger G, Gronberg H, Aly M, Nordström T, Pharoah P, Pashayan N, Schleutker J, Tammela TLJ, Sipeky C, Auvinen A, Albanes D, Weinstein S, Wolk A, Hakansson N, West C, Dunning AM, Burnet N, Mucci L, Giovannucci E, Andriole G, Cussenot O, Cancel-Tassin G, Koutros S, Freeman LEB, Sorensen KD, Orntoft TF, Borre M, Maehle L, Grindedal EM, Neal DE, Donovan JL, Hamdy FC, Martin RM, Travis RC, Key TJ, Hamilton RJ, Fleshner NE, Finelli A, Ingles SA, Stern MC, Rosenstein B, Kerns S, Ostrer H, Lu YJ, Zhang HW, Feng N, Mao X, Guo X, Wang G, Sun Z, Giles GG, Southey MC, MacInnis RJ, FitzGerald LM, Kibel AS, Drake BF, Vega A, Gómez-Caamaño A, Fachal L, Szulkin R, Eklund M, Kogevinas M, Llorca J, Castaño-Vinyals G, Penney KL, Stampfer M, Park JY, Sellers TA, Lin HY, Stanford JL, Cybulski C, Wokolorczyk D, Lubinski J, Ostrander EA, Geybels MS, Nordestgaard BG, Nielsen SF, Weisher M, Bisbjerg R, Røder MA, Iversen P, Brenner H, Cuk K, Holleczek B, Maier C, Luedeke M, Schnoeller T, Kim J, Logothetis CJ, John EM, Teixeira MR, Paulo P, Cardoso M, Neuhausen SL, Steele L, Ding YC, De Ruyck K, De Meerleer G, Ost P, Razack A, Lim J, Teo SH, Lin DW, Newcomb LF, Lessel D, Gamulin M, Kulis T, Kaneva R, Usmani N, Slavov C, Mitev V, Parliament M, Singhal S, Claessens F, Joniau S, Van den Broeck T, Larkin S, Townsend PA, Aukim-Hastie C, Gago-Dominguez M, Castelao JE, Martinez ME, Roobol MJ, Jenster G, van Schaik RHN, Menegaux F, Truong T, Koudou YA, Xu J, Khaw KT, Cannon-Albright L, Pandha H, Michael A, Kierzek A, Thibodeau SN, McDonnell SK, Schaid DJ, Lindstrom S, Turman C, Ma J, Hunter DJ, Riboli E, Siddiq A, Canzian F, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Kraft P, Freedman M, Wiklund F, Chanock S, Henderson BE, Easton DF, Haiman CA, Eeles RA, Conti DV, and Kote-Jarai Z
- Subjects
- Algorithms, Bayes Theorem, Black People genetics, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Molecular Sequence Annotation, Multivariate Analysis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, White People genetics, Prostatic Neoplasms genetics
- Abstract
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
- Published
- 2018
- Full Text
- View/download PDF
21. Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium.
- Author
-
Lophatananon A, Stewart-Brown S, Kote-Jarai Z, Al Olama AA, Garcia SB, Neal DE, Hamdy FC, Donovan JL, Giles GG, Fitzgerald LM, Southey MC, Pharoah P, Pashayan N, Gronberg H, Wiklund F, Aly M, Stanford JL, Brenner H, Dieffenbach AK, Arndt V, Park JY, Lin HY, Sellers T, Slavov C, Kaneva R, Mitev V, Batra J, Spurdle A, Clements JA, Easton D, Eeles RA, and Muir K
- Abstract
This corrects the article DOI: 10.1038/bjc.2017.231.
- Published
- 2018
- Full Text
- View/download PDF
22. Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium.
- Author
-
Lophatananon A, Stewart-Brown S, Kote-Jarai Z, Olama AAA, Garcia SB, Neal DE, Hamdy FC, Donovan JL, Giles GG, Fitzgerald LM, Southey MC, Pharoah P, Pashayan N, Gronberg H, Wiklund F, Aly M, Stanford JL, Brenner H, Dieffenbach AK, Arndt V, Park JY, Lin HY, Sellers T, Slavov C, Kaneva R, Mitev V, Batra J, Spurdle A, Clements JA, Easton D, Eeles RA, and Muir K
- Subjects
- Aged, Case-Control Studies, Gene-Environment Interaction, Humans, Male, Middle Aged, Neoplasm Grading, Polymorphism, Single Nucleotide, Prostatic Neoplasms epidemiology, Prostatic Neoplasms pathology, Risk Assessment, Body Height genetics, Prostatic Neoplasms genetics
- Abstract
Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer., Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions., Results: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01-1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group., Conclusions: There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.
- Published
- 2017
- Full Text
- View/download PDF
23. Polymorphisms in androgen metabolism genes AR, CYP1B1, CYP19, and SRD5A2and prostate cancer risk and aggressiveness in Bulgarian patients.
- Author
-
Kachakova D, Mitkova A, Popov E, Beltcheva O, Vlahova A, Dikov T, Christova S, Mitev V, Slavov C, and Kaneva R
- Subjects
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Aromatase, Case-Control Studies, Cytochrome P-450 CYP1B1, Genetic Predisposition to Disease, Genotype, Humans, Male, Membrane Proteins, Prostatic Neoplasms, Receptors, Androgen, Polymorphism, Genetic
- Abstract
Background/aim: The aim of our study was to elucidate the role of polymorphisms in AR, CYP1B1, CYP19, and SRD5A2 genes for prostate cancer (PC) development in Bulgarian patients., Materials and Methods: We genotyped 246 PC patients and 261 controls (155 with benign prostate hyperplasia and 107 healthy population controls) using direct sequencing, PCR-RFLP, SSCP, and fragment analysis., Results: The allele and genotype frequencies of most of the studied variants did not differ significantly between cases and controls. Increased frequencies of the C/C genotype and C allele of rs1056837 in CYP1B1, and genotype 7/8 of the (TTTA)n repeat polymorphism in CYP19, were observed in patients in comparison with controls.The 8/9 and the 7/12 genotypes of (TTTA)n in CYP19 showed suggestive evidence for association with decreased prostate cancer risk and the risk for aggressive disease, respectively. The haplotype analysis revealed 2 CYP1B1 haplotypes associated with PC risk reduction., Conclusion: Some CYP1B1 haplotypes and genotypes of the CYP19 (TTTA)n repeat appeared to be associated with disease risk or aggressiveness in Bulgarian PC patients. In contrast, the SRD5A2 polymorphisms (V89L and (TA)n repeat), the CAG repeat in AR, and the Arg264Cys variant in CYP19A1 are most likely not implicated in prostate carcinogenesis.
- Published
- 2016
- Full Text
- View/download PDF
24. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.
- Author
-
Gusev A, Shi H, Kichaev G, Pomerantz M, Li F, Long HW, Ingles SA, Kittles RA, Strom SS, Rybicki BA, Nemesure B, Isaacs WB, Zheng W, Pettaway CA, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, John EM, Murphy AB, Signorello LB, Carpten J, Leske MC, Wu SY, Hennis AJ, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Witte JS, Casey G, Kaggwa S, Cook MB, Stram DO, Blot WJ, Eeles RA, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Gronberg H, Wiklund F, Aly M, Henderson BE, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright L, Teerlink C, Brenner H, Dieffenbach AK, Arndt V, Park JY, Sellers TA, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Spurdle A, Clements JA, Teixeira MR, Pandha H, Michael A, Paulo P, Maia S, Kierzek A, Conti DV, Albanes D, Berg C, Berndt SI, Campa D, Crawford ED, Diver WR, Gapstur SM, Gaziano JM, Giovannucci E, Hoover R, Hunter DJ, Johansson M, Kraft P, Le Marchand L, Lindström S, Navarro C, Overvad K, Riboli E, Siddiq A, Stevens VL, Trichopoulos D, Vineis P, Yeager M, Trynka G, Raychaudhuri S, Schumacher FR, Price AL, Freedman ML, Haiman CA, and Pasaniuc B
- Subjects
- Acetylation, Atlases as Topic, Cell Line, Tumor, Genetic Loci, Genome-Wide Association Study, Histones genetics, Histones metabolism, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms ethnology, Prostatic Neoplasms pathology, Black or African American, Epigenesis, Genetic, Genetic Predisposition to Disease, Inheritance Patterns, Prostatic Neoplasms genetics, White People
- Abstract
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
- Published
- 2016
- Full Text
- View/download PDF
25. The S-layer Protein DR_2577 Binds Deinoxanthin and under Desiccation Conditions Protects against UV-Radiation in Deinococcus radiodurans.
- Author
-
Farci D, Slavov C, Tramontano E, and Piano D
- Abstract
Deinococcus radiodurans has the puzzling ability to withstand over a broad range of extreme conditions including high doses of ultraviolet radiation and deep desiccation. This bacterium is surrounded by a surface layer (S-layer) built of a regular repetition of several proteins, assembled to form a paracrystalline structure. Here we report that the deletion of a main constituent of this S-layer, the gene DR_2577, causes a decrease in the UVC resistance, especially in desiccated cells. Moreover, we show that the DR_2577 protein binds the carotenoid deinoxanthin, a strong protective antioxidant specific of this bacterium. A further spectroscopical characterization of the deinoxanthin-DR_2577 complex revealed features which could suggest a protective role of DR_2577. We propose that, especially under desiccation, the S-layer shields the bacterium from incident ultraviolet light and could behave as a first lane of defense against UV radiation.
- Published
- 2016
- Full Text
- View/download PDF
26. Genome-wide association study of prostate cancer-specific survival.
- Author
-
Szulkin R, Karlsson R, Whitington T, Aly M, Gronberg H, Eeles RA, Easton DF, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Southey MC, FitzGerald LM, Henderson BE, Schumacher FR, Haiman CA, Sipeky C, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah PD, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubiński J, Kluźniak W, Cannon-Albright L, Brenner H, Herrmann V, Holleczek B, Park JY, Sellers TA, Lim HY, Slavov C, Kaneva RP, Mitev VI, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Batra J, Clements JA, Albanes D, Andriole GL, Berndt SI, Chanock S, Gapstur SM, Giovannucci EL, Hunter DJ, Kraft P, Le Marchand L, Ma J, Mondul AM, Penney KL, Stampfer MJ, Stevens VL, Weinstein SJ, Trichopoulou A, Bueno-de-Mesquita BH, Tjønneland A, Cox DG, Maehle L, Schleutker J, Lindström S, and Wiklund F
- Subjects
- Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide genetics, Prostatic Neoplasms genetics, Survival Analysis, Prostatic Neoplasms mortality
- Abstract
Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical., Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR)., Results: We observed no significant association between genetic variants and prostate cancer survival., Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study., Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF
27. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans.
- Author
-
Amin Al Olama A, Dadaev T, Hazelett DJ, Li Q, Leongamornlert D, Saunders EJ, Stephens S, Cieza-Borrella C, Whitmore I, Benlloch Garcia S, Giles GG, Southey MC, Fitzgerald L, Gronberg H, Wiklund F, Aly M, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, Mcdonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokołorczyk D, Kluzniak W, Cannon-Albright L, Brenner H, Butterbach K, Arndt V, Park JY, Sellers T, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Govindasami K, Guy M, Lophatonanon A, Muir K, Viñuela A, Brown AA, Freedman M, Conti DV, Easton D, Coetzee GA, Eeles RA, and Kote-Jarai Z
- Subjects
- Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Chromosome Mapping methods, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics, White People genetics
- Abstract
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region., (© The Author 2015. Published by Oxford University Press.)
- Published
- 2015
- Full Text
- View/download PDF
28. Two different mechanisms cooperate in the desiccation-induced excited state quenching in Parmelia lichen.
- Author
-
Slavov C, Reus M, and Holzwarth AR
- Subjects
- Chlorophyll chemistry, Fungal Proteins metabolism, Kinetics, Photosystem I Protein Complex chemistry, Photosystem I Protein Complex metabolism, Photosystem II Protein Complex metabolism, Spectrometry, Fluorescence, Temperature, Fungal Proteins chemistry, Photosystem II Protein Complex chemistry, Saccharomycetales metabolism
- Abstract
The highly efficient desiccation-induced quenching in the poikilohydric lichen Parmelia sulcata has been studied by ultrafast fluorescence spectroscopy at room temperature (r.t.) and cryogenic temperatures in order to elucidate the quenching mechanism(s) and kinetic reaction models. Analysis of the r.t. data by kinetic target analysis reveals that two different quenching mechanisms contribute to the protection of photosystem II (PS II). The first mechanism is a direct quenching of the PS II antenna and is related to the characteristic F740 nm fluorescence band. Based on the temperature dependence of its spectra and the kinetics, this mechanism is proposed to reflect the formation of a fluorescent (F740) chlorophyll-chlorophyll charge-transfer state. It is discussed in relation to a similar fluorescence band and quenching mechanism observed in light-induced nonphotochemical quenching in higher plants. The second and more efficient quenching process (providing more than 70% of the total PS II quenching) is shown to involve an efficient spillover (energy transfer) from PS II to PS I which can be prevented by a short glutaraldehyde treatment. Desiccation causes a thylakoid-membrane rearrangement which brings into direct contact the PS II and PS I units. The energy transferred to PS I in the spillover process is then quenched highly efficiently in PS I due to the formation of a long-lived P700(+) state in the dried state in the light. As a consequence, both PS II and PS I are protected very efficiently against photodestruction. This dual quenching mechanism is supported by the low temperature kinetics data.
- Published
- 2013
- Full Text
- View/download PDF
29. Evaluation of the clinical value of the newly identified urine biomarker HIST1H4K for diagnosis and prognosis of prostate cancer in Bulgarian patients.
- Author
-
Kachakova D, Mitkova A, Popov E, Beltcheva O, Vlahova A, Dikov T, Hristova S, Mitev V, Slavov C, and Kaneva R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Case-Control Studies, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Prostate-Specific Antigen blood, Prostatic Hyperplasia genetics, Prostatic Hyperplasia urine, Prostatic Neoplasms genetics, Prostatic Neoplasms urine, Real-Time Polymerase Chain Reaction, Young Adult, Biomarkers, Tumor urine, DNA Methylation, Histones genetics, Promoter Regions, Genetic genetics, Prostatic Hyperplasia diagnosis, Prostatic Neoplasms diagnosis
- Abstract
Purpose: Searching for diagnostic and prognostic biomarkers for prostate cancer (PC) is main public health priority. DNA methylation in body fluids is a stable, easily detectable and promising PC biomarker. The major advantages of urine-based assays are their noninvasive nature and the ability to monitor PC with heterogeneous foci. The aim of this study was to determine the diagnostic value of the recently identified candidate PC biomarker HIST1H4K., Methods: We investigated DNA methylation of HIST1H4K in urine samples from 57 PC patients, 29 controls with benign prostatic hyperplasia (BPH) and 50 young asymptomatic men (YAM) by MethyLight real-time PCR., Results: The frequency of HIST1H4K promoter hypermethylation significantly discriminated PC patients from YAM (AUC =0.763; 95% CI 0.672-0.839; p<0.0001), but did not show any statistical difference between PC patients and BPH controls (AUC=0.513, 95% CI 0.402-0.622; p=0.8255). HIST1H4K could not outperform the prostatic specific antigen (PSA) in our sample (AUC=0.785; 95% CI 0.679-0.870; p<0.0001). Methylation of HIST1H4K showed significant correlation with aging (r=0.5418; p<0.0001), but with no other clinicopathological characteristics., Conclusion: The results suggest that the promoter hypermethylation of HIST1H4K is rather due to aging than related to prostate carcinogenesis. To elucidate this observation analysis of larger samples is needed.
- Published
- 2013
30. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.
- Author
-
Amin Al Olama A, Kote-Jarai Z, Schumacher FR, Wiklund F, Berndt SI, Benlloch S, Giles GG, Severi G, Neal DE, Hamdy FC, Donovan JL, Hunter DJ, Henderson BE, Thun MJ, Gaziano M, Giovannucci EL, Siddiq A, Travis RC, Cox DG, Canzian F, Riboli E, Key TJ, Andriole G, Albanes D, Hayes RB, Schleutker J, Auvinen A, Tammela TL, Weischer M, Stanford JL, Ostrander EA, Cybulski C, Lubinski J, Thibodeau SN, Schaid DJ, Sorensen KD, Batra J, Clements JA, Chambers S, Aitken J, Gardiner RA, Maier C, Vogel W, Dörk T, Brenner H, Habuchi T, Ingles S, John EM, Dickinson JL, Cannon-Albright L, Teixeira MR, Kaneva R, Zhang HW, Lu YJ, Park JY, Cooney KA, Muir KR, Leongamornlert DA, Saunders E, Tymrakiewicz M, Mahmud N, Guy M, Govindasami K, O'Brien LT, Wilkinson RA, Hall AL, Sawyer EJ, Dadaev T, Morrison J, Dearnaley DP, Horwich A, Huddart RA, Khoo VS, Parker CC, Van As N, Woodhouse CJ, Thompson A, Dudderidge T, Ogden C, Cooper CS, Lophatonanon A, Southey MC, Hopper JL, English D, Virtamo J, Le Marchand L, Campa D, Kaaks R, Lindstrom S, Diver WR, Gapstur S, Yeager M, Cox A, Stern MC, Corral R, Aly M, Isaacs W, Adolfsson J, Xu J, Zheng SL, Wahlfors T, Taari K, Kujala P, Klarskov P, Nordestgaard BG, Røder MA, Frikke-Schmidt R, Bojesen SE, FitzGerald LM, Kolb S, Kwon EM, Karyadi DM, Orntoft TF, Borre M, Rinckleb A, Luedeke M, Herkommer K, Meyer A, Serth J, Marthick JR, Patterson B, Wokolorczyk D, Spurdle A, Lose F, McDonnell SK, Joshi AD, Shahabi A, Pinto P, Santos J, Ray A, Sellers TA, Lin HY, Stephenson RA, Teerlink C, Muller H, Rothenbacher D, Tsuchiya N, Narita S, Cao GW, Slavov C, Mitev V, Chanock S, Gronberg H, Haiman CA, Kraft P, Easton DF, and Eeles RA
- Subjects
- Case-Control Studies, Disease Progression, Humans, Male, Odds Ratio, Polymorphism, Single Nucleotide, Reproducibility of Results, Genetic Predisposition to Disease, Genome-Wide Association Study, Prostatic Neoplasms genetics, Quantitative Trait Loci
- Abstract
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
- Published
- 2013
- Full Text
- View/download PDF
31. Independent initiation of primary electron transfer in the two branches of the photosystem I reaction center.
- Author
-
Müller MG, Slavov C, Luthra R, Redding KE, and Holzwarth AR
- Subjects
- Electron Transport, Kinetics, Models, Molecular, Spectrum Analysis methods, Photosystem I Protein Complex chemistry
- Abstract
Photosystem I (PSI) is a large pigment-protein complex that unites a reaction center (RC) at the core with approximately 100 core antenna chlorophylls surrounding it. The RC is composed of two cofactor branches related by a pseudo-C2 symmetry axis. The ultimate electron donor, P(700) (a pair of chlorophylls), and the tertiary acceptor, F(X) (a Fe(4)S(4) cluster), are both located on this axis, while each of the two branches is made up of a pair of chlorophylls (ec2 and ec3) and a phylloquinone (PhQ). Based on the observed biphasic reduction of F(X), it has been suggested that both branches in PSI are competent for electron transfer (ET), but the nature and rate of the initial electron transfer steps have not been established. We report an ultrafast transient absorption study of Chlamydomonas reinhardtii mutants in which specific amino acids donating H-bonds to the 13(1)-keto oxygen of either ec3(A) (PsaA-Tyr696) or ec3(B) (PsaB-Tyr676) are converted to Phe, thus breaking the H-bond to a specific ec3 cofactor. We find that the rate of primary charge separation (CS) is lowered in both mutants, providing direct evidence that the primary ET event can be initiated independently in each branch. Furthermore, the data provide further support for the previously published model in which the initial CS event occurs within an ec2/ec3 pair, generating a primary ec2(+)ec3(-) radical pair, followed by rapid reduction by P(700) in the second ET step. A unique kinetic modeling approach allows estimation of the individual ET rates within the two cofactor branches.
- Published
- 2010
- Full Text
- View/download PDF
32. Trap-limited charge separation kinetics in higher plant photosystem I complexes.
- Author
-
Slavov C, Ballottari M, Morosinotto T, Bassi R, and Holzwarth AR
- Subjects
- Energy Transfer, Fluorescence, Kinetics, Light-Harvesting Protein Complexes chemistry, Time Factors, Arabidopsis enzymology, Photosystem I Protein Complex chemistry, Photosystem I Protein Complex metabolism
- Abstract
Time-resolved fluorescence measurements were performed on isolated core and intact Photosystem I (PS I) particles and stroma membranes from Arabidopsis thaliana to characterize the type of energy-trapping kinetics in higher plant PS I. Target analysis confirms the previously proposed "charge recombination" model. No bottleneck in the energy flow from the bulk antenna compartments to the reaction center has been found. For both particles a trap-limited kinetics is realized, with an apparent charge separation lifetime of approximately 6 ps. No red chlorophylls (Chls) are found in the PS I-core complex from A. thaliana. Rather, the observed red-shifted fluorescence (700-710 nm range) originates from the reaction center. In contrast, two red Chl compartments, located in the peripheral light-harvesting complexes, are resolved in the intact PS I particles (decay lifetimes 33 and 95 ps, respectively). These two red states have been attributed to the two red states found in Lhca 3 and Lhca 4, respectively. The influence of the red Chls on the slowing of the overall trapping kinetics in the intact PS I complex is estimated to be approximately four times larger than the effect of the bulk antenna enlargement.
- Published
- 2008
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.